Currently, the most common practice for replacing damaged or diseased bone is to use autograft (bone removed from the patient). However, high incidences of donor site morbidity, the necessity of a painful second ‘harvesting’ surgical procedure, and the absence of large quantities of bone available for grafting compromises patient outcomes. Concerns with allografts (bone taken from a cadaver) and xenografts (bone obtained from animals) include: (1) transmission of disease, (2) difficulty of procurement and processing, (3) uncertain immune response, and (4) premature resorption.
As a consequence of the limitations associated with ‘natural’ grafts, there is significant advantage for the development of synthetic bone grafts that have the potential to offer important advantages, including: elimination of the risk of disease transmission; reduced occurrence of an adverse immunological response; absence of painful ‘harvesting’ procedure; relatively low costs; unlimited supply; and the ability to incorporate pharmaceutical agents that accelerate the bone healing process.
As the main inorganic component of bone consists of a highly substituted calcium phosphate (CaP) apatite, researchers concerned with developing synthetic bone substitutes have concentrated on the various forms of CaP. These include hydroxyapatite, carbonated apatite, fluroapatite, α and β tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, and combinations thereof. In general, these materials have proven to be both biocompatible and osteoconductive and are well tolerated by host tissues. However, to be an effective bone substitute, these materials must possess the appropriate physical structure and mechanical properties. Of particular concern, structurally, is the level of porosity, pore size, and size of the interconnections between each pore.
Currently commercially available synthetic bone grafts possess low levels of porosity, inappropriate pore size and pore size distribution, and inadequate pore connectivity to permit vascularization of the implant and, thus, do not adequately support tissue in-growth. Another disadvantage of commercially available bone grafts is their poor mechanical properties, which limits the use of these implants to non-load bearing applications. Furthermore, the techniques used to manufacture these implants do not permit the production of porous bodies with gradient porosity or those with a solid cortical shell; necessary properties for applications involving segmental defects.
Mechanical fixation of orthopedic implants can lead to the unintentional release of particulate debris that can migrate into surrounding tissues or articular joints. The presence of this debris can compromise the vitality of surrounding tissues or damage articular surfaces, leading to bone resorption, osteolysis and the failure of such implants over time. As such, another major disadvantages of commercially available synthetic bone grafts is the risk of particulate debris generation and migration arising from the use of standard orthopedic fixation techniques.
There are several patents describing methods of producing porous bodies for use as bone replacements; see for example, U.S. Pat. Nos. 3,899,556, 3,929,971, 4,654,314, 4,629,464, 4,737,411, 4,371,484, 5,282,861, 5,766,618, 5,863,984, WO 95/32008 and WO99119003. A common technique for producing porous ceramic bodies involves the use of pore forming agents as described in U.S. Pat. Nos. 4,629,464, 4,654,314, 3,899,556 and WO 95/32008. Pore forming agents, however, typically result in a ‘closed cell’ structure characterized by inadequate pore interconnectivity. It is well known that tissue in-growth into porous materials is a function of both pore size and pore connectivity. Many researchers have attempted to overcome this lack of pore connectivity by increasing the fraction of pore forming agents used and, whilst this does slightly improve pore connectivity, the accompanying loss of mechanical strength makes the resulting structure impractical for clinical use.
U.S. Pat. No. 4,737,411 discloses a method for producing porous ceramics. In this method, a ceramic composite having an open porous network and a controlled pore size is produced by coating ceramic particles, of known size, with a glass coating. These coated ceramic particles were subsequently pressed into the desired shape and sintered such that the glass coating fused the ceramic particles together. Through the close control of the particle size and thickness of the glass coating, the size of the pores formed between the fused particles could be controlled. This technique of forming porous ceramics for bone replacement is somewhat limited, as the maximum pore size obtainable is approximately 150 μm, whilst previous research has shown that pore sizes up to 500 μm are required for optimum tissue in-growth.
U.S. Pat. No. 3,299,971 discloses a method of producing a porous synthetic material for use in hard tissue replacement. In this method, a porous carbonate skeletal material of marine life (coral) is converted into a porous hydroxyapatite material through a hydrothermal chemical exchange with a phosphate. The final microstructure of the converted hydroxyapatite material is essentially the same as that of the coral from which it was formed. Consequently, pore size is dependent on the type of coral used. While these porous structures possess the appropriate pore size and pore connectivity for hard tissue in-growth, the structure is limited to that of the selected coral and so the production of implants with a solid shell surrounding the porous network (typical of cortical or long bone, for example) is unobtainable. In addition, the bone grafts manufactured using this technique are characterized by poor mechanical properties and are difficult to handle and shape and cannot be secured using standard fixation techniques.
Reticulated foams made from an organic material, such as polyurethane, are characterized by pore interconnectivity, high porosity, and are available in a variety of pore sizes. As such, these reticulated structures have been used to manufacture porous bodies of metal or ceramic composition. While typically used in molten metal filtration applications, both ceramic and metal foams manufactured from the coating of reticulated polyurethane networks have found increasing use in orthopaedic and dentistry applications. For example, U.S. Pat. No. 5,282,861 discloses a reticulated carbon foam (converted from polyurethane using a thermal treatment) that was used to manufacture an open cell tantalum foam for use as an implant in both hard and soft tissue. Tantalum was applied to the surface of the carbon foam as a thin film using a chemical vapour deposition (CVD) technique. As such, the Tantalum-coated foam replicated closely the morphology of the reticulated carbon foam substrate. While Tantalum is biocompatible (i.e. inert), it is non-degradable and non-resorbable and, as such, will be implanted permanently. This is also the case with total hip and knee replacements and, while the titanium and cobalt alloys used to fabricate these implants are also considered to be ‘biocompatible’, long-term implantation of these devices often results in adverse systemic effects such as metal ion sensitization. As a consequence of these problems, it is becoming increasingly desirable to use, where possible, an implant that will eventually be resorbed and replaced with natural, healthy bony tissue.
U.S. Pat. No. 3,946,039 discloses a method to produce porous ceramic or metal structures using reticulated polyurethane foam. In this method a reticulated polyurethane foam is invested with an inorganic composition that is not compromised by the processing conditions required for forming the reticulated ceramic or metal structure. The polyurethane foam structure is removed using a chemical or thermal process, and the voids remaining in the investment are filled with a fluid composition (metal or ceramic) to form a reticulated casting. The final step of this process involves dissolving the investment so as to leave the reticulated ceramic or metal foam structure casting. The disadvantages of this technique are similar to that of the coral conversion method in that the structure of the final part is limited to the structure of the starting foam. Furthermore, the incorporation of a solid outer shell or density gradients is difficult or unobtainable.
Perhaps the most common technique for producing porous bodies from reticulated polyurethane foam is a replication technique, as disclosed in U.S. Pat. Nos. 4,371,484, 6,136,029, 3,947,363, 4,568,595, 3,962,081, 4,004,933, 3,907,579, 5,456,833 and WO 95/32008. In general, this technique involves impregnating a reticulated polyurethane foam structure with a metal or ceramic slurry to deposit a thin film of coating material onto the surface of the foam substrate. Excess slurry is commonly removed from the pores by passing the foam through a set of rollers, centrifuging, or blasting with a jet of air. After the excess slurry has been removed, the reticulated structure is dried and the organic foam substrate removed by pyrolysis. This typically involves heating to temperatures between 200° C. and 500° C. After the pyrolysis of the foam substrate, the temperature is increased for the subsequent sintering of the metallic or ceramic particles.
U.S. Pat. Nos. 5,456,833 and 4,568,595 describe two different methods for forming a solid shell of material around a coated reticulated structure. The former describes the use of a pressed annular ring around a reticulated cylinder while the latter indicates the use of a secondary process where a high viscosity slurry is applied to the outside of the reticulated structure to generate a solid coating following thermal processing in order to improve the strength of the reticulated structure.
U.S. Pat. No. 6,136,029 discloses a method to produce a porous structure suitable for bone substitution comprising a continuous, strong, framework structure of alumina or zirconia using the standard replication technique. In an attempt to provide osteoconductive and/or osteoinductive properties to the porous implant, a second material of osteoconductive/osteoinductive composition was included. The second material could be present in several forms, including (1) a coating on the surface of the framework structure, (2) in the form of a composite, intimately mixed with the framework material, or (3) as a porous mass within the interstices of the framework structure. The second phase materials outlined as being suitable for this invention included osteoconductive materials such as collagen and the various forms of calcium phosphate (hydroxyapatite, tricalcium phosphate, etc.) and osteoinductive materials such as bone morphogenetic proteins (BMP's), demineralized bone matrix, and transforming growth factors (TGF-β). The variations to the foam replication process as outlined in this patent are important in bone substitution applications as they provide a means to produce a composite implant capable of delivering pharmaceutical agents that may enhance the rate of healing. However, the use of an inert framework structure as a means of providing the implant with improved mechanical properties severely limits the use of this device for hard tissue replacement. As previously mentioned, it is desirable that the implanted material be completely replaced with natural bony tissue.
As the repair or replacement of bony voids or defects is site specific, pharmaceutical agents, such as bone growth factors, must be locally delivered via an appropriate carrier. Biodegradable polymers have been used as drug delivery vehicles as they can be implanted directly at the site of repair and their rate of degradation and, hence, rate of drug delivery can be controlled. However, such biodegradable polymers do not possess the mechanical properties suitable for hard tissue replacement. As such, there has been an increased interest in polymeric/ceramic composites, as disclosed for example U.S. Pat. No. 5,766,618 and WO 99/19003.
U.S. Pat. No. 5,766,618 describes a method of forming a polymer/ceramic composite in which a biocompatible and biodegradable polymer (PLGA) was combined with a calcium phosphate ceramic (hydroxyapatite) in an attempt to improve the mechanical properties of the polymer matrix. While the incorporation of a ceramic phase provided an initial improvement in elastic modulus, immersion of the implant in a simulated physiological environment resulted in a rapid decrease in modulus from 1459 MPa to less than 10 MPa in under six weeks. Clearly, such rapid degradation of mechanical properties limits the use of this device for hard tissue replacement applications.
WO 99/19003 describes an injectable polymer/ceramic gel that is fluid under non-physiological conditions and non fluid under physiological conditions. Composed of natural or synthetic, resorbable or non-resorbable polymers mixed with a ceramic phase, the gel is limited to filling very small bony defects and does not possess the mechanical properties or porous structure for the treatment of large segmental defects.
It is apparent from the aforementioned prior art that a variety of methods have been developed to manufacture porous implants suitable for bone repair and/or replacement. However, current methods and implants possess several shortcomings that make the resultant function of the implant less than satisfactory for prolonged implantation. It would therefore be advantageous to develop a porous implant and method of making such that obviates the shortcomings of the prior art.
The Applicant's U.S. Pat. No. 6,323,146 discloses a synthetic biomaterial compound (Skelite™) composed of silicon-stabilized calcium phosphate. Extensive testing demonstrated that this compound is ideally suited for use as a bone substitute material as it is: (1) 100% synthetic, (2) biocompatible, (3) able to participate in the body's natural bone remodeling process, and (4) relatively inexpensive to produce. U.S. Pat. No. 6,323,146 also describes a method of forming a porous body of the Skelite™ compound by replicating a reticulated organic foam substrate. It is now demonstrated that the synthetic biomaterial compound can be incorporated with a biodegradable polymer in such a manner to provide a variety of implants that possess sufficient mechanical strength to be used as a bone substitute in both load-bearing and non-load bearing applications and further overcomes the disadvantages associated with implants of the prior art.